PROJECT SUMMARY Chemotherapy-induced peripheral neuropathy (CIPN) occurs in approximately 60% of patients who receive neurotoxic chemotherapy agents. Symptoms of CIPN include burning/shooting pain, tingling, cramping, and numbness in the hands and feet. CIPN is associated with impaired balance, walking, and sleep, decreased quality of life, and falls. Few, only minimally effective treatments are available for CIPN; these pharmacologic treatments are rarely evidenced-based, potentially addictive, and contribute to polypharmacy. Some research suggests that CIPN results from abnormal neuronal processing in the central and peripheral nervous systems, including decreased central descending inhibitory mechanisms. Data suggests that transcutaneous electrical nerve stimulation (TENS) relieves symptoms in other neuropathic pain conditions, partly by activating central descending inhibitory pathways, but this mechanism has yet to be investigated for TENS in CIPN. The proposed research aims to investigate the preliminary efficacy of TENS, a safe, inexpensive, non-pharmacologic treatment for CIPN. A rigorous phase II, multi-site, patient- and assessor-blinded randomized clinical trial (RCT) that investigates physiologic and psychologic mechanisms and leverages the NCI Community Oncology Research Program (NCORP) for efficiency is proposed. The purpose of the study is to obtain data to inform the conduct of a confirmatory, phase III RCT. The proposed TENS device is a patient- controlled, wireless unit that can conveniently be worn throughout the day during physical activity; the unit is ideal for maximizing adherence in clinical trials and for optimizing dissemination in clinical practice. The primary aim of the study is to obtain preliminary efficacy estimates (effect sizes and confidence intervals) of TENS on a composite measure of CIPN (CIPN20). Secondary aims include obtaining (1) preliminary efficacy estimates for individual CIPN symptoms (0 ? 10 numeric rating scales), (2) preliminary efficacy of TENS on activity and balance in patients with CIPN, (3) effects of TENS on central descending inhibitory mechanisms in CIPN patients, and (4) feasibility data for conducting a patient- and assessor-blinded RCT of TENS in the multi-site NCORP Research Network. This phase II RCT is an integral step in a program of research that will rigorously evaluate the efficacy of TENS for CIPN. Establishing effective, non-pharmacologic treatments for CIPN will help to mitigate suffering in cancer survivors while avoiding potentially harmful side effects caused by many currently available analgesic drugs.